Development and Evaluation of 2-Amino-7-Fluorophenazine 5,10-Dioxide Polymeric Micelles as Antitumoral Agents for 4T1 Breast Cancer

Abstract

2-Amino-7-fluorophenazine 5,10-dioxide (FNZ) is a bioreducible prodrug, poorly soluble in water, with potential anticancer activity on hypoxic-tumors. This poor solubility limits its potential applications in clinic. Amphiphilic pristine polymeric micelles (PMs) based on triblock copolymers Pluronic® and Tetronic®, glycosylated derivatives and their mixtures with preformed-liposomes (LPS), were analyzed as strategies to improve the bioavailability of FNZ. FNZ encapsulations were performed and the obtaining nanostructures were characterized using UV-visible spectroscopy (UV-VIS), Transmission Electron Microscopy (TEM), Fourier transform infrared analysis and Dynamic Light Scattering (DLS). The most promising nanoformulations were analyzed for their potential toxicity and pharmacologically, at 20 mg/kg FNZ-doses, in a stage-IV murine metastatic-breast tumor model. The results revealed that the solubility of the encapsulated-FNZ increased up to seven times and the analysis (UV-VIS, DLS and TEM) confirmed the interaction between vehicles and FNZ. In all the cases appropriate encapsulation efficiencies (up to 70%), monodisperse nanometric particle sizes (PDI = 0.180–0.335), adequate Z-potentials (−1.59 to −26.4 mV), stabilities and spherical morphologies were obtained. The in vitro profile of FNZ controlled releases corresponded mainly to a kinetic Higuchi model. The in vitro/in vivo biological studies revealed non-toxicity and relevant tumor-weight diminution (up to 61%).

The Phenazine Scaffold Used as Cytotoxic Pharmacophore Applied in Bactericidal, Antiparasitic and Antitumor Agents

“…Furthermore, the 7‐fluoro‐2‐aminophenazine‐PDO ( 6 ) displayed in vitro bioreductive selective cytotoxicity towards solid tumors in hypoxic regions [75] . Some in vivo preclinical studies carried out in BALB/c female mice bearing 4T1‐breast‐tumor as a murine model confirmed its antitumor activity by the quantification of a decrease in tumor size, animals’‐survival, and biochemical/hematological data [56] . The combination of PDO derivatives with an incorporated benzyl group, e. g ., 7(8)‐bromo‐2‐(4‐nitrobenzyloxy)‐PDO, 7(8)‐bromo‐2‐(4‐chlorobenzyloxy)‐PDO and 7(8)‐bromo‐2‐(4‐methylthiobenzyloxy)‐PDO ( 7 ) are new selective hypoxic cytotoxins with additional ability to inhibit DNA topoisomerase II activity [57] .…”

“…[75] Some in vivo preclinical studies carried out in BALB/c female mice bearing 4T1-breast-tumor as a murine model confirmed its antitumor activity by the quantification of a decrease in tumor size, animals'survival, and biochemical/hematological data. [56] The combination of PDO derivatives with an incorporated benzyl group, e. g., 7(8)-bromo-2-(4-nitrobenzyloxy)-PDO, 7(8)-bromo-2-(4-chlorobenzyloxy)-PDO and 7(8)bromo-2-(4-methylthiobenzyloxy)-PDO (7) are new selective hypoxic cytotoxins with additional ability to inhibit DNA topoisomerase II activity. [57] Hernández et al [58] showed the chemosensitizer effect of the PDO analogs such as 8 to cisplatin and the mechanism of action on bladder cancer cells.…”

“…[15] Thus, TMP substitution at position C(2) on the phenazine core of riminophenazines enhanced their anti-plasmodial activity. Moreover, TMP-derivatives B4119 (53), B4125 (52), B4126 (55), B4100 (56), and B4103 (57) were active against Grampositive pathogens MRSA Staphylococcus aureus and MDR Streptococcus pneumoniae showing 100 % or 90 % activity, at concentrations of 2 μg/mL, and they have very high activity against Enterococci. [251] Franzblau et al [252] found that the anti-Mycobacterium leprae activity of TMP-substituted phenazines in the in vitro assay generally increased with substitutions of the Hatoms on the phenyl and aniline groups by EtO or Me moieties, and halogens.…”

“…Compound B4090 (59) was also studied by using the kinetic method of drug evaluation in the mouse food pad model of leprosy (with CFM-resistant M. smegmatis strain) and did not cause pigmentation of the mouse fed at a concentration of 0.01 % in the diet. [179] Thus, TMP-substituted phenazines B4090 (59), B4100 (56), and B3786 (60) with potent activity against CFMresistant M. leprae strain in the in vitro assay [165,252] are good candidates for leprosy treatment because they did not cause any problems with the skin discolor-ation. In turn, B4128 (61) inhibited MDR carcinoma cell lines [253] and the growth of M. aurum A + as well as MT H 37 Ra at the concentration of 0.6 and 2.5 μg/mL, respectively.…”

Indocyanine green within glycosylated polymeric micelles as potential image agents to map sentinel lymph nodes and breast cancer

“…15 In particular, there has been a great increase in the use of pristine block copolymers, Pluronic® and Tetronic®, for tumour diagnosis and therapy, in response to their FDA approval. [16][17][18][19] Notable features are their unique aqueous selfassembly properties and core-shell structure based on amphiphilic copolymers formed by one hydrophobic backbone of poly( propylene oxide) (PPO), flanked by hydrophilic poly(ethylene oxide) (PEO) chains, [16][17][18] which can be advantageous when ICG is used for molecular cancer diagnosis. Chiefly, we have found that PMs preferentially accumulate in solid tumours and capitalize on their characteristics, such as the high vascularization, poor lymphatic clearance, and slow venous return, via the enhanced permeability and retention (EPR) effect that has been widely reported in different nanosystems.…”